1 2-disubstituted-5-nitroimidazoles

ABSTRACT

METHODS OF PREPARING 2-CYANO-1-LOWERALKYL-5-NITROIMIDAZOLES AND 1-LOWER-ALKANOYLOXY-LOWER-ALKYL-2-CYANO5-NITROIMIDAZOLES AND NOVEL INTERMEDIATES RESULTING FROM RELATED 1-SUBSTITUTED-2-METHYL-5-NITRONIMIDAZOLES ARE DESCRIBED. SOME OF THE COMPOUNDS ARE ACTIVE AS ANALGESICS. ANTIPARASITICS AND DIURETICS AND OTHERS ARE USEFUL AS INTERMEDIATES TO PRODUCE ANTIBACTERIAL AGENTS SUCH AS 2-(2AMINO-5-THIADIAZOLYL)-1-METHYL-5-NITROIMIDAZOLE.

United States Patent 3,652,555 1,2-DISUBSTITUTED-S-NITROIMIDAZOLES Jay Donald Albright, Nanuet, and Robert Gordon Shepherd, South Nyack, N.Y., assignors to American Cyanamid Company, Stamford, Conn. No Drawing. Filed June 16, 1969, Ser. No. 833,683 Int. Cl. C07d 49/36 US. Cl. 260-240 D 6 Claims ABSTRACT OF THE DISCLOSURE Methods of preparing 2-cyano-1-loweralkyl-S-nitroimidazoles and 1-lower-a1kanoyloxy-lower-alkyl-2-cyano- S-nitroimidazoles and novel intermediates resulting from related 1-substituted-Z-methyl-S-nitroirnidazoles are described. Some of the compounds are active as analgesics, antiparasitics and diuretics and others are useful as intermediates to produce antibacterial agents such as 2-(2- amino-S-thiadiazolyl)-l-methyl-S-nitroimidazole.

SUMMARY OF THE INVENTION This invention relates to novel syntheses of new 1- loWer-alkyl-S-nitroimidazoles and l-loweralkanoyloxyloweralkyl-S-nitroi.midazoles with novel substituents in the 2-position. More specifically, the invention relates to novel processes for converting l-lower-alkyl, l-hydroxylower-alkyl, 1-loweralkanoyloxy-lower-alkyl and l-benzoyloxy-lower-alkyl-Z-methyl-S-nitroimidazoles to l-loweralkyl, 1-loweralkanoyloxy-lower-alkyl and l-benzoyloxylower-alkyl-S-nitroimidazoles containing a nitrile at the C-2 position or certain functional groups convertible to nitrile.

It is the object of this invention to provide new methods which give condensation reactions on the Z-methyl group of l-lower alkyl, l-hydroxy-lower-alkyl, l-loweralkanoyloxy-lower alkyl and 1-benzoyloxy-lower-alkyl2-methyl- S-nitroimidazoles. Heretofore such reactions have been largely unsuccessful; the principal previously reported reaction involving condensation on the Z-methyl group of 1-substituted-2-methyl-S-nitroimidazoles is the reaction with benzaldehyde to give styryl derivatives as described in Netherlands Pat. No. 6413815.

It is the further object of this invention to provide new processes for the preparation of new intermediates leading to l-lower-alkyl, 1-loweralkanoyloxy-lower-alkyl and 1-benzoyloxy-1oweralky1-2-cyano-S-nitroimidazoles.

The novel present compounds can be illustrated as those of the formula:

Mrs-

wherein R is selected from the group consisting of lower alkyl,

-CHzCH2O IC---loweralkyl and C2H40 C-Rg and R is selected from the group consisting of CH=C CH2( R2 and wherein R is selected from the group consisting of phenyl, monohalophenyl, dihalophenyl, trihalophenyl, lower alkylphenyl, dilower alkylphenyl, triloweralkylphenyl, p-nitrophenyl, t-butyl, naphthyl, trifiuoromethyl,

Ice

pyridyl and lower carboalkoxy. The term loweralkyl is intended to cover those of 1-4 carbon atoms.

The present compounds are crystalline solids, soluble in a number of organic solvents but relatively insoluble in water.

The compounds of the present invention are prepared from 1-lower-alkyl-, l-hydroxy-lower-alkyl-, l-loweralkanoyloxy-lower-alkyl-, or 1-benzoyloxyloweralkyl-2- methyl-S-nitroimidazole (I) by reaction with from 2 to about 8 moles of an acid halide at a temperature of about 25C. to 125 C. for 3 to 24 hours in an inert solvent in the presence of a tertiary amine such as, for example, triethylamine or diisopropylethylamine. Acid halides found useful in the reaction may be, for example, benzoyl chloride, halobenzoyl chloride, dihalobenzoyl chlorides, trihalobenzoyl chlorides, lower alkylbenzoyl chlorides, dilower alkyl benzoyl chlorides, trilower alkylbenzoyl chlorides, p-nitrobenzoyl chloride, pivalyl chloride, naphthoyl chloride, pyridylcarbonylchloride, benzoyl bromide or trifiuoroacetyl fluoride. Solvents such as tetrahydrofuran, diglyme, benzene, toluene, and the like can be used.

A suflicient quantity of a tertiary amine such as diisopropylethylamine is used both to catalyze the reaction and to react with the hydrogen halide liberated. For example, refluxing 0.2 mole of 1,2-dimethyl-S-nitroimidazole and 0.6 mole of benzoyl chloride in 125 ml. of diisopropylethylamine and ml. of dioxane for 18 hours gives 1- methyl-S-nitro a phenyI-Z-imidazoleethenol benzoate in high yield. Hydrolysis of the enol benzoate under standard acidic or basic conditions then yields 2-(1-methyl-5- nitro 2 imidazolyl)acetophenone (III, R=CH and R =phenyl, fiowsheet hereinafter), which is a key intermediate in the synthesis of Z-cyano-l-methyl-S-nitrm imidazole. In the case of 1-hydroxy-lower-alkyI-Z-methyl- S-nitroimidazoles, 1 equivalent of a loweralkanoyl halide is consumed in forming the ester of the hydroxy group on the hydroxylower alkyl substitutent. Thus, 0.1 moles of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole reacted under the above conditions with 0.4 moles of benzoyl chloride gives 1-(2-benzoyloxyethyl)-2-methyl-5-nitroimidazole-u-phenylethenol benzoate, mild hydrolysis of which yields 2- 1- (2-benzoyloxyethyl) -5-nitro-2-imidazolylJacetophenone. The latter is converted to l-(2- benzoyloxyethyl)-2cyano-5-nitroimidazole, which can be hydrolyzed to 2-cyanol-(2-hydroxyethyl)-5-nitroimidazole, a useful intermediate for the preparation of antimicrobially active nitroimidazole carboxamides (US. Pat. 3,341,549) and ntroimidazolyl aminothiadiazoles.

Nitrosation of (l-lower-alkyl or l-loweralkanoyloxylower-alkyl-S-nitro 2-imidazolyl)methyl ketones (III) yields the a-oximino ketones (TV) which are useful intermediates in the synthesis of l-lower-alkyl, l-loweralkanoyloxyloweralkyl or 1-benzoyloxy-lower-alkyl-2-cyano-S-nitroimidazoles (V). The nitrosation of derivatives of structural type (III) may be carried out with alkyl nitrites such as, for example, isoamyl nitrite and butyl nitrite under either acidic or basic conditions in the conventional manner. Alternatively, nitrous acid, nitrosylsulfuric acid or nitrosyl chloride may be used; however, the preferred procedures involve reaction of a (l-loweralkyl, 1-loweralkanoyloxy-lower-alkyl or l-benzoyloxy-loweralkyl-S-nitro-2-imidazolyl)methyl ketone derivative (III) with a metal nitrite, such as sodium or potassium nitrite in acetic acid at a temperature of about 0 C. to C. or alternatively, the nitration of (II) to give (IV) directly can be carried out using nitrosyl sulfuric acid, for example.

Cleavage of the l-oxirnino-l-(l-lower-alkyl or l-loweralkanoyloxy lower alkyl 5-nitro-2-imidazolyl)-2-substituted glyoxals (IV) to 2-cyano l-lower-alkyl or 1- loweralkanoyloxy-lower-alkyl-S-nitroimidazoles (V) may be carried out by heating the glyoxals above 200 C. or by reaction with reagents such as thionyl bromide, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosgene, oxalyl chloride, p-toluenesulfonyl chloride and the like. In addition, other reagents suitable for catalysis of Beckmann rearrangements or oximes may be employed. The preferred procedure involves reaction with thionyl chloride or phosphorus pentachloride at about 25 C. to 80 C. for 10 minutes to 3 hours. Cleavage of some glyoxals, namely, the ethyl l-lower-alkyl-S-nitro- 01,13 dioxo 2 imidazolepropionate B oximes (IV, R =CO loweralkyl) to 2 cyano 1 loweralkyl 5- nitroimidazoles (V) is carried out by mild heating at 50 C. to 100 C. The above reactions are shown on the following Flowsheet:

o N oii a H5 1a,,coc1 I a 1! 0a f R;

I II

H or on i? (E ca ca 0,, n

mom moo-so r:

N ii if 4 It e t N O N N o I a I NOH wherein R and R are as hereinbefore defined, and where R is hydroxyloweralkyl in Compound I, it is loweralkanoyloxy lower alkyl in the ensuing compounds in the Flowsheet.

The compounds of the present invention such as lrnethyl S-nitro-a-phenyl-Z-imidazoleethenol benzoate are active as analgesics and diuretics. Analgesic activity can be determined by the following method. The procedure is based upon the reduction of the number of writhes following the intraperitoneal injection of 1 milligram .per kilogram of body weight of phenyl-p-quinone (PPQ) in male Swiss Albino mice obtained weekly from Monor Farms, the mice weighing 15-25 grams per mouse at the time of use. The syndrome is characterized by intermittent contractions of the abdomen, twisting and turning of the trunk and extension of the hind legs beginning 3 to minutes after injection. Control mice show the syndrome continuously for more than 30 minutes. A compound is considered active if it reduces the total number of writhes in 2 test mice from an historical control value of approximately 30 per pair to a value of 18 or less (counted for a 3 minute period of time, minutes after injection of PPQ). The test is repeated, using 2 more mice. The com- 4 pound is considered inactive if the number of writhes per pair exceeds 18 in either test. The compound is considered active if the number of writhes per pair is 18 or less in both tests.

Some of the compounds of this invention have shown diuretic properties as determined by animal experiments as follows: Mature male rats weighing between 180 and 300 grams are allowed a normal fluid intake prior to testing. The single oral administration of the test compound is given 0.5 milliliter of 2 percent aqueous starch suspension. Four cages (2 rats per cage) serve as controls for each measurement. Control animals receive only the starch suspension. After administration, the test animals are placed in metabolism cages. Observations of the amount of urine excreted are made after 5 hours and after 24 hours. The final values recorded are the ratios of the amount of urine excreted by the test rats to the amount of urine excreted by the control rats. Sodium and potassium concentrations in the urine are determined by flame photometry, and chloride concentrations are measured by mercurimetric titration.

The present compounds are useful intermediates for the preparation of 1 lower alkyl 5 nitro 2 imidazolecarboxamides which have anti-parasitic activity. The compound 2-cyano-1-methyl-5-nitroimidazole is useful as an intermediate in the preparation of 2-(2-amino-l,3,4-thiadiazol 5 yl) 1-methyl-5-nitroimidazole described in Science, 162, page 1146 (1968) as a highly active antibacterial and antiparasitic agent.

The compounds 2-cyano-1-lower-alkyl-S-nitroimidazole can be converted into, for example, 2 (2 amino-1,3,4- thiadiazol-S-yl)-1-methyl-5-nitroimidazole by the following procedure. A 2-cyano-l-loWer-alkyl-5-nitroimidazole is admixed with an absolute alcohol such as methanol, ethanol or the like, and heated in the presence of a strong base such as an alkali metal alkoxide, including potassium t-butoxide and sodium ethoxide, to yield a l-lower alkyl- 5-nitroimidazole-Z-carboximidate. The carboximidate is then converted to the imidazolecarboximidolyl acylhydrazide. amidinohydrazine, semicarbazide or thiosemicarbazide by reaction with an acylhydrazine, aminoguanidine, semicarbazide or thiosemicarbazide, respectively. This reaction is preferably carried out in the presence of an inert solvent such as loweralkanol, glacial acetic acid or aqueous alcoholic mixtures and at an elevated temperature usually between about 50 C. and C. although somewhat higher or lower temperatures may be employed.

Cyclization of the thus prepared imidazolecarboximidoylacylhydrazines, amidinohydrazines, or semicarbazides then yields the triazol-3-yl-5 nitroimidazoles. Cyclization of the imidazolecarboximidoylthiosemicarbazides gives 2-(Z-amino-1,3,4-thiadiazol-5-yl)-5-nitroimidazoles. These reactions, in the case of the triazol-3-yl-5-nitroimidazoles, are generally most favorably carried out by heating, preferably refluxing, in the presence of an organic solvent such as nitrobenzene, dimethylformamide or glacial acetic acid. In the case of the thiadiazol-S-yl-S- nitroimidazoles acidic reagents such as concentrated sulfuric acid or aqueous hydrochloric acid are advantageously employed.

SPECIFIC DISCLOSURE The invention will be described in greater detail in conjunction with the following specific examples. The followmg examples are given for the purpose of illustration and not intended to limit the scope of the invention.

EXAMPLE 1 Preparation of 1-methyl-5-nitro-a-phenyl-2-imidazoleethenol benzoate (A) A mixture of 28.7 g. (0.020 mole) of 1,2-dimethyl-S-nitroimidazole, ml. of diisopropylethylamine, 75 ml. of dioxane and 70 ml. (84 g.; 0.60 mole) of benzoyl chloride is refluxed for 18 hours. After standing and cooling to room temperature, 300 ml. of ether is added to the crystalline mass. The solid is broken up and filtered and washed with ether. The solid is washed with two 100-ml. portions of water and with ether to give 59 g. of l-methyl- S-nitro oz phenyl-Z-imidazoleethenol benzoate, melting point l94-198 C., raised to 205-207 C. by recrystallization as in Example 2A.

(B) Trimethylamine, 33.8 g., 0.573 moles, is dissolved in 120 ml. toluene. This solution is mixed with 20 g., 0.1416 moles 1,Z-dimethyl-S-nitroimidazole and 41 ml., 0.3540 mole of benzoyl chloride. The mixture is mechanically stirred overnight at about room temperature. The resulting bright yellow precipitate is filtered, mixed with 50 ml. water, washed three times with a total of 150 ml. water and dried in a hot air oven to constant weight. There is obtained 47.7 g. (97%), of product, melting point 200 to 202 C., and 205207 C. after recrystallization. This compound has activity against Trichomonas vaginalis.

Other compounds which are prepared according to the above-described procedure are, for example,

l-methyl-S-nitro-a- 4-chlorophenyl -2-imidazoleethanol 4-chlorobenzoate;

l-methyl- 5-nitro-u- 2,4-dichlorophenyl -2-imidazoleethenol 2,4-dichlorobenzoate, and

l-methyl 5 nitro-w(2,4,6-tribromophenyl)-2-irnidazoleethenol 2,4,6-tribrmobenzoate.

EXAMPLE 2 Preparation of 1-methyl-5-nitro-a-phenyl-2-imidazoleethenol benzoate (A) A mixture of 5.64 g. (0.040 mole) of 1,2-dimethyl-S-nitroirnidazole, 20 ml. of diisopropylethylamine, 15 ml. of dry dioxane and 6.19 g. (0.044 mole) of benzoyl chloride is stirred and refluxed for 19.5 hours. The mix ture is chilled, diluted with 50 ml. of ether and filtered. The solid is washed with water and dried to give 6.2 g. of 1-methyl-S-nitro-a-pheny1-2-imidazoleethenol benzoate as yellow crystals, melting point 185190 C. Recrystallization of a g. sample from a mixture of 400 ml. of ethanol, 100 ml. of chloroform and 150 ml. of tetrahydrofuran gives 3.9 g. of product as yellow crystals, melting point 205207 C.

(B) A mixture of 5 g. (0.0354 moles) of 1,2-dimethyl- S-nitroimidazole, 24 ml. (0.17 moles) triethylamine, 13 ml. dioxane and 12.4 ml. (0.1082 mole) of benzoyl chloride is stirred at room temperature for one hour. The resulting bright yellow precipitate is filtered, washed with ether, then with water and dried. There is obtained 9.8 g. (80%) of product, melting point 194 to 197 C., and 205207 C., after recrystallization.

The following compounds are prepared according to the above-described procedure:

1-methyl-5-nitro-a- 4-nitrophenyl) -2-imidazoleethenol 4-nitrobenzoate;

1-methyl-5-nitro-a- (4-methylphenyl -2-imidazoleethenol 4-methylbenzoate;

l-methyl-S -nitro-a- 2,4-dimethylphenyl) -2-imidazoleethenol 2,4-dimethylbenzoate and l-methyl 5 nitro-a-(2,4-dimethoxyphenyl)-2-imidazoleethenol 2,4-dimethoxybenzoate.

EXAMPLE 3 Preparation of 1-methyl-5-nitro-a-phenyl-2-imidazoleethenol benzoate A mixture of 5.64 g. (0.040 mole) of 1,2-dimethyl-5- nitroimidazole, 25 ml. of diisopropylethylamine, ml. of dry dioxane and 11.5 g. (0.082 mole) of benzoyl chloride is stirred and refluxed for 18 hours. The solution is chilled, diluted with 100 ml. of ether and filtered. The solid is washed with ether and with water and dried to give 8.1 g. of l-methyl 5 nitro a phenyI-Z-imidazoleethenol benzoate as yellow crystals, melting point 200- 203 C., and 205-207" C., after recrystallization.

Other compounds prepared according to the abovedescribed procedure are, for example, 1-methyl-5-nitr0-anaphthyl-2-irnidazoleethenol naphthoate or l-methyl-S- nitro-ot- (4fluorophenyl) -2-imidazoleethenol 4-fluorobenzoate.

EXAMPLE 4 Preparation of 1-ethyl-5-nitro-ot-phenyl-2-imidazoleethenol benzoate -A mixture of 7.75 g. (0.050 mole) of 1-ethyl-2-methyl- 5-nitroimidazole, 25 ml. of diisopropylethylamine, 15 ml. of dioxane and 21.1 g. (0.15 mole) of benzoyl chloride is refluxed for 5.5 hours. The mixture is chilled, diluted with ml. of ether and filtered. The solid is washed with 25 ml. of ether and with water to give 6.7 g. of product. Recrystallization from ethanol gives 5.4 g. of l-ethyl-S- nitro-a-phenyl-2-imidazoleethenol benzoate as yellow needles, melting point 151 C.

Other compounds are prepared according to the abovedescribed procedure, for example,

1-ethyl-5-nitro-u-naphthyl-2-imidazoleethenol naphthoate;

1-ethyl-5-nitro-a- (4-bromophenyl) -2-imidazoleethenol 4-bromobenzoate;

1-ethyl-5-nitro-a- 2,4-dimethylphenyl) -2-imidazoleethenol 2,4-dimethylmenzoate;

l-ethyl S-nitro-a- 2,4-dichlorophenyl) 2-imidazoleethenol 2,4-dichlorobenzoate; 0r

l-ethyl-S-nitro-a- (2,4-dimeth0xyphenyl -2-imidazoleethenol 2,4-dimethoxybenzoate.

EXAMPLE 5 Preparation of 2- 1-methyl-5-nitro-2-imidazolyl) acetophenone A mixture of 1.75 g. (0.0050 mole) of 1-methyl-5- nitrO-a-phenyI-Z-imidazoleethenol benzoate in 10 ml. of 'water, 15 m1. of ethanol and 10 ml. of concentrated hydrochloric acid is refluxed for 18 hours. The solution is chilled, poured onto ice and the pH of the solution adjusted to ca. 5 with 10 N sodium hydroxide. The mixture is filtered and the solid washed with water and once with ether to give 0.9 g. of 2 (1 methyl 5 nitro-2- imidazolyl) -acetophenone as yellow crystals, melting point 137141 C.

Other compounds are prepared using the above-described procedure, for example,

p-methoxy-2( 1-methyl-5-nitro-2-imidazolyl -acetophenone;

p-fluoro-2 1-methyl-5-nitro-2-imidazolyl acetophenone;

o,p-dichloro-2( 1-methyl-5-nitro-2-imidazoly1) acetophenone; or

p-nitro-2( 1-methyl-5-nitro-2-imidazolyl acetophenone.

EXAMPLE 6 Preparation of p-chloro-2(1-methyl-5-nitro-2-imidazolyl) acetophenone A solution of 0.032 mole of potassium hydroxide in 150 ml. of ethanol is stirred at about 25 C. as 0.30 mole of 1,2-dimethyl-S-nitroimidazole and 0.60 mole of chlorobenzaldehyde are added rapidly. The mixture is stirred for about 3 hours, the resulting precipitate is filtered, washed with ethanol and dried. There is obtained l-p-chlorophenyl 2 (1 methyl 5 nitro-Z-imidazolyl) ethanol.

A mixture of 1.41 g. (0.0050 mole) of l-p-chlorophenyl-2-(1-methyl-5-nitro-2-imidazolyl)ethanol, 4 ml. of dry dimethyl sulfoxide and 1.9 ml. (0.02 mole) of acetic anhydride is stirred at room temperature for 20 hours. The mixture is poured onto ice and allowed to stand at room temperature for two hours. The mixture is filtered and the solid washed with Water to give 1.3 g. of product. Recrystallization from ethanol gives 0.76 g. of product, melting point 165-175 C. which is purified by partition chromatography to give p-chloro-2-(l-methyl-S-nitro-Z- imidazolyl)acetophenone, melting point -163 C.

7 EXAMPLE 7 Preparation of 2-(1methyl-5-nitro-2-imidazolyl) acetophenone A solution of 1.8 g. (0.032 mole) of potassium hydroxide in 150 ml. of ethanol is stirred at about 25 C. as 42.3 g. (0.30 mole) of 1,2-dimethyl--nitroimidazole and 63.6 g. (0.60 mole) of benzaldehyde are added rapidly. The mixture is stirred for about 3 hours, the resulting precipitate filtered, washed with ethanol and dried. There is obtained 65.4 g. of l-phenyl-2-(1-methyl-5-nitro-2- imidazolyl)ethanol, melting point 172176.5 C.

1-phenyl-2-(1-methyl 5 nitro 2 imidazolyl)ethanol (4.94 g., 0.02 mole) is dissolved in ml. of dimethyl sulfoxide, 7.5 ml. (0.080 mole) of acetic anhydride is added, and the solution is purged with nitrogen for 5 minutes. The flask is then stoppered and the solution is stirred at room temperature overnight. The mixture is cooled in an ice bath and 22.5 ml. of water is added. After continued cooling and trituration, the gummy solid solidifies and is filtered and washed with water to yield 4.78 g. of solid. Purification gives 2-(1-methyl-5-nitro- Z-imidazolyl)acetophenone as pale yellow crystals.

EXAMPLE 8 Preparation of 1-oximino-l-( l-methyl-S-nitro-Z- imidazolyl)-2-phenylglyoxal To a mixture of 1.7 g. (0.0060 mole) of 2-(1-methyl- 5 nitro 2 imidazolyl)acetophenone hydrochloride and 0.76 g. (0.0090 mole) of potassium nitrite is added 15 ml. of glacial acetic acid. The solid dissolves and the reaction mixture becomes warm (ca. 50 C.). After standing for one-half hour, the mixture is filtered and the solid washed with acetic acid to give 0.8 g. of l-oximino-l-(lmethyl-5-nitro-2-imidazolyl)-2-phenylglyoxal as pale yellow crystals, melting point 188490 C.

EXAMPLE 9 Preparation of 1-oximino-1-(l-methyl-5-nitro-2- imidazolyl)-2-phenylglyoxal To a mixture of 2.45 g. (0.010 mole) of 2-(1-methyl- 5-nitro-2-imidazolyl)acetophenone and ml. of glacial acetic acid cooled in an ice bath is added 1.3 g. (0.015 mole) of potassium nitrite. The mixture is stirred at 5- 10 C. for 10 minutes and allowed to warm to room temperature and stirred for 1.5 hours. The mixture is chilled, filtered and the solid washed with 5 ml. of glacial acetic acid and with water to give 2.0 g. of l-oximino-l-(lmethyl-S-nitro-Z-imidazolyl)-2-phenylglyoxal as pale yellow crystals, melting point 184-187 C.

Other compounds are prepared according to the abovedescribed procedure, for example,

1-oximino-l-(1-methyl-5-nitro-2-imidazolyl)-2-(4- chlorophenyl glyoxal; 1-oximino-1-(1-methyl-5-nitro-2-imidazolyl)-2-(4- nitrophenyl) glyoxal; 1-oxirnino-1-(1-methyl-5-nitro-2-imidazolyl)-2-(2,4-

dibromophenyl glyoxal; 1-oximino-1-(1-methyl-5-nitro-2-imidazolyl)-2-(4- rnethylphenyl)glyoxal, or 1-oximino-1-(1-methyl-5-nitro-2-imidazolyl)-2-naphthyl glyoxal, 1-oximino-1-[1-(2-acetoxyethyl)-5-nitro-{3-imidazolyl]-2- phenylglyoxal, or 1-oximino-1-[ l-(2-benzoyloxyethyl)-5-nitro-2-imidazoly]]-2-phenylglyoxal.

EXAMPLE 10 Preparation of l-oximino-2-(1-methyl-5-nitro-2- imidazolyl)-2-phenylglyoxal To a mixture of 2.45 g. (0.010 mole) of 2-( l-methyl-S- nitro-2-imidazolyl)acetophenone in ml. of dry tetrahydrofuran and 6 ml. of diisopropylethylamine is added 3.5 g. (0.03 mole) of isoamylnitrite. The mixture is stirred at room temperature under nitrogen for four days. The solvent is removed under reduced pressure and the solid filtered and Washed with ethanol. The solid is triturated with acetic acid and filtered to give 1-oximino-1-( l methyl-5- nitro-Z-imidazolyl) 2 phenylglyoxal, melting point 183187 0.

EXAMPLE 11 Preparation of 1-oximino-1-(l-methyl-S-nitro- 2-imidazolyl) -2-phenylglyoxal To a mixture of 2.45 g. (0.010 mole) of 2-(1-methyl- 5-nitro-2-imidazolyl)acetophenone in 10 ml. of dry methanol and 10 ml. of dry tetrahydrofuran is added 0.54 g. (0.010 mole) of sodium methoxide. To this mixture chilled to 0 C. is added 2.6 ml. (0.020 mole) of isoamylnitrite. The mixture is stirred at room temperature for 2 hours and glacial acetic acid is added to bring the pH to ca. 6.5. The solvent is removed under reduced pressure and the residue triturated with ether and filtered to give the product 1-oximino-1-(1-methyl-5-nitro-2-imidazolyl -2-phenylglyoxal.

EXAMPLE 12 Preparation of 1-oximino-1-( l-methyl-S-nitro- Z-imidazolyl -2-phenylglyoxal To a stirred suspension of 2.45 g. (0.010 mole) of 2- (1-rnethyl-5-nitro-2-imidazolyl)acetophenone in 175 ml. of ether and 30 ml. of ethanol cooled in an ice bath is added 2.6 ml. of isoamylnitrite. Dry hydrogen chloride is bubbled into the mixture for 10 minutes and 50 ml. of tetrahydrofuran added. The mixture is stirred at 0 C. for 15 minutes and at room temperature for 1.5 hours. The mixture is filtered and the filtrate concentrated under reduced pressure. The residue is triturated with ether and filtered. The solid is suspended in ethanol-water (1:1) and the pH brought to 7 with sodium bicarbonate solution. The mixture is diluted with water and filtered to give 1.0 g. of crude product. Recrystallization from aqueous ethanol with the aid of activated carbon gives 0.6 g. of 1-oximino-1-(1-methyl-5-nitro-2-imidazolyl)-2-phen ylglyoxal. Further recrystallizations give the product as white crystals, melting point l84186 C.

EXAMPLE 13 Preparation of 2-eyano-1-methyl-5-nitroimidazole To 1.37 g. 1-oximino-l-(l-methyl-5-nitro-2-imidazolyl)-2-phenylglyoxal (0.0050 mole) is added 5 ml. of thionyl chloride. After standing at room temperature for 10 minutes, the mixture is warmed on a steam bath until the solution began to reflux. After standing for two hours at room temperature, the excess thionyl chloride is removed under reduced pressure. The oily residue is poured onto ice and the mixture brought to ca. pH 7.5 with concentrated ammonium hydroxide. The mixture is extracted with ether and the ether extract concentrated under reduced pressure. The residual solid is triturated with cold methanol to give 0.30 g. of 2-cyano-1-methyl- S-nitroimidazole, melting point 81-84 C. From the filtrate there is obtained in several crops, an additional 0.26 g. of product, melting point -84 C.

Other compounds which are useful in accordance with the above-described procedure to give 2-cyano-l-methyl- 5-nitroimidazole are, for example,

1-oximino-1-( 1-methyl-5-nitro-2-imidazolyl) 2- (4-fiuorophenyl) glyoxal;

1-oximino-l-( 1-methyl-5-nitro-2-imidazolyl 2- (4-methoxypheny1 glyoxal;

1-oximine-1-( 1-methyl-5-nitro-2-imidazolyl) 2- a-pyridyl) glyoxal;

1-oximino-1-(1-methyl-5-nitro-2-imidazolyl)- 2- (2,4-dichlorophenyl glyoxal,

l-oximino-1-( l-methyl-S-nitro-2-imidazolyl) 2-naphthylglyoxal.

EXAMPLE 14 Preparation of 2-cyano-1-methyl-5-nitroimidazole A 0.245 g. sample (0.0010 mole) of l-oximino-l-(lmethyl-S-nitro-Z-imidazolyl)-2-phenylglyoxal is heated at 210 C. in an oil bath for five minutes. The dark liquid is dissolved in chloroform and filtered through aluminum oxide. The aluminum oxide is washed with chloroform and the filtrate and washings are combined and concentrated under reduced pressure. The residue is dissolved in methanol and the crystals which separated are filtered off. The filtrate is allowed to evaporate to a gum and the gum extracted with ether. Concentration of the ether extract gives the product 2-cyano-1-methyl-5-nitroimidazole.

EXAMPLE 15 Preparation of 1-oximino-1-(1-methyl-5-nitro- 2-imidazolyl)-2-phenylglyoxal To 5 ml. of cooled concentrated sulfuric acid is added 1.74 g. 2-(l-methyl-5-nitro 2 imidazolyDacetophenone followed by 0.64 g. of potassium nitrite. The mixture is stirred at room temperature for 40 minutes, poured onto ice, diluted with water and filtered. The solid is washed thoroughly with water to give 156 g. of l-oximino-l-(lmethyl-S-nitro 2 imidazolyl)-2-phenylglyoxal as yellow crystals, melting point 175-180 C.

EXAMPLE 16 Preparation of 1-oximino-1-(l-methyl-S-nitro- 2-imidazolyl)-2-phenylglyoxal (A) To 7 ml. of concentrated sulfuric acid chilled to 0 C. is added 0.64 g. (0.0075 mole) of potassium nitrite. The mixture is diluted with 4 ml. of glacial acetic acid and 1.75 g. (0.0050 mole) of 1-methyl-5-nitro-aphenyl-2-imidazoleethenol benozate is added. The mixture is stirred at room temperature for minutes and is warmed on a steam bath to 50 C. After stirring at room temperature for "V2 hour, the mixture is poured into a mixture of ice and 10 ml. of 10 N sodium hydroxide. The mixture (ca. 100 ml.) is filtered and the solid washed thoroughly with water to give 1.1 g. of l-oximino-l-(lmethyl-S-nitro 2 imidazolyl)-2-phenylglyoxal as yellow crystals, melting point 173179 C.

(B) A mixture of g. (0.0573 mole) of l-methyl-S- nitrQ-a-phenyI-Z-imidazoleethenol benzoate, 150 ml. of ethanol, 120 ml. of distilled water and 120 ml. of concentrated hydrochloric acid is refluxed for four hours. The resulting orange solution is divided into two parts, (1) 200 ml., and (2) 200 ml. which are worked up as follows: 1) is partially neutralized by adding 20.3 g. sodium bicarbonate with stirring to a pH less than 2, and to the resulting suspension 5.95 g. (0.086 mole) of sodium nitrite is added portionwise and stirred at room temperature for about one hour. The resulting product is filtered, washed thoroughly with water and dried in hot air overnight. There is obtained 7.6 g. (97%) of product, melting point 187 to 189 C. (2) To the stirred solution is added 5.95 g. (0.086 mole) of sodium nitrate over one hour. The reaction mixture is stirred overnight (17 hours) and the resulting precipitate filtered, washed with water and dried in hot air. There is obtained 6.8 g. (87%) of product, melting point 190 to 191 C.

EXAMPLE 17 Preparation of 1-oximino-1-(1-ethyl-5-nitro-2-imidazolyl) -2-phenylglyoxal To 10 ml. of concentrated sulfuric acid is added 6.0 g. of a 54% solution of nitrosylsulfuric in 104% sulfuric acid. The solution is diluted with 5 ml. of acetic acid and 7.27 g. of 1-ethyl-S-nitro-a-phenyl-Z-imidazoleethenol benzoate is added. The mixture is stirred and chilled occasionally. After one-half hour, the mixture is poured onto ice, and the solid is filtered off. The solid is washed thoroughly 10 with water to give 4.0 g. of 1-oximino-1-(1-ethyl-5-nitro- 2-imidazolyl)-2-phenylgloxal as tan crystals, melting point 155165 C. Recrystallization from ethanol with the aid of activated carbon gives 2.9 g. of product as tan crystals, melting point 165167 C.

EXAMPLE 18 Preparation of ethyl 1-methyl-5-nitro-2-imidazolepyruvate (A) To a mixture of 5.64 g. (0.040 mole) of 1,2- dimethyl-5-nitroimidazole, 50 ml. of toluene and 10 ml. of triethylamine is added 6.14 g. (0.045 mole) of ethyl oxalyl chloride. The mixture is stirred at room temperature for 22 hours and filtered. The solid is washed with ether and then with water to give 2.8 g. of ethyl l-carboethoxy-2-( l-methyl 5 nitno 2 imidazolyl)vinyloxalate as pale yellow crystals, melting point 117120 C. The solid is dissolved in hot ethanol and the solution chilled and filtered to give 1.6 g. of ethyl 1-methyl-5-nitro-2-imidazolepyruvate as orange crystals, melting point 137- 139 C.

(B) To a mixture of 5.64 g. of 1,2-dimethyl-5-nitroimidazole, 50 ml. of toluene and 20 ml. of triethylamine is added 12.28 g. (0.090 mole) of ethyl oxalyl chloride. The mixture is stirred at room temperature for 24 hours and is diluted with 75 ml. of ether. The solid is filtered off, washed with ether and then with water to give 6 .9 g. of ethyl 1-carboethoxy-2-(l-methyl 5 nitro 2 imidazolyl)vinyloxalate, melting point 118120 C. The solid is dissolved in ml. of hot ethanol and the solution chilled to give 4.4 g. of ethyl l-methyl-S-nitro-Z-imidazolepyruvate as orange crystals, melting point 140-142 C.

EXAMPLE 19 Preparation of ethyl 1-methyl-5-nitro-a,B-dioxo-2-imidazolepropionate fi-oxime and conversion to 2-cyano-1- methyl-5-nitroimidazole To a suspension of 1.2 g. (0.005 mole) of ethyl l-methyl-5-nitro-2-imidazolepyruvate in 15 ml. of glacial acetic acid is added 0.80 g. (0.0095 mole) of potassium nitrite. The mixture is stirred at room temperature for 20 minutes and the solvent removed under reduced pressure. The residue is dissolved in water and the solution brought to pH 7 with 10 N sodium hydroxide. The mixture is extracted with chloroform, and the chloroform extracts dried over magnesium sulfate and concentrated under reduced pressure. The residual oil of crude ethyl 1-methyl-5-nitro-a,/3-dioxo-2-imidazolepropionate p-oxime is heated on a steam bath for 15 minutes and on cooling there is obtained 0.65 g. of 2-cyano-l-methyl-S-nitroimidazole.

EXAMPLE 20 Preparation of 1-(2-benzoyloxyethyl)-5-nitro-2-imidazole-a-phenylethenol benzoate To a stirred mixture of I-(Z-hydroxyethyl)-2-methyl S-nitroimidazole (8.55 g., 0.05 mole) and triethylamine (41.4 ml., 0.30 mole) in 200 ml. of toluene is added benzoyl chloride (34.8 ml., 0.30 mole). The refluxing mixture is stirred and heated at reflux for 41 hours. The mixture is cooled and the triethylamine hydrochloride is filtered. The filtrate is evaporated to dryness and the residue is slurried with a mixture of 100 ml. of heptane and 70 ml. of toluene. The solid is filtered, affording a sticky brown solid. This solid is slurried with 100 ml. of 95% ethanol and the bright yellow solid is filtered, washed and dried, producing 7.5 g. of the desired compound. This compound has a melting point of 159-161 C. Substitution of an equimolar quantity of l-(2-acetoxyethyl)-2 methyl-S-nitroimidazole for 1,2-dimethyl-5-nitroimidazole in Example 1B gives I-(Z-acetoxyethyl)-5-nitro-ot-phenyl Z-imidazoleethenol benzoate.

1 1 EXAMPLE 21 Preparation of 2-[1-(2-benzoyloxyethyl)-5-nitro-2- imidazolyl] -acetophenone To 0.242 g. of 1-(2-benzoyloxyethyl)-5-nitro-2-imidazole-u-phenylethenol benzoate is added 1 ml. of cone. hydrochloric acid, 5 ml. water and ml. 95% ethanol. The heterogeneous mixture is refluxed for 5 /2 hours at which time it is homogeneous. Cooling and filtering yield the title ketone which is recrystallized from chloroform-hexane to give crystals melting at 160-1 C.

By a similar procedure using a shortened reaction time, 2-[1-(2-acet0xyethyl)-5-nitro 2 imidazolyl1acetophenone is prepared from its enol benzoate.

EXAMPLE 22 Preparation of 1-(2-acetoxyethyl)-2-cyano- 5-nitroimidazole The method of Example 13 when applied to l-oximinol-[l-(2-acetoxyethyl)-5-nitro 2 imidazolyl]-2-phenylglyoxal gives 1-(2-acetoxyethyl)-2-cyano 5 nitroimidazole. Substitution of phosphorus tetrachloride in toluene for thionyl chloride results in formation of the same product.

EXAMPLE 23 Preparation of 1-(2-benzoyloxyethyl) 2 cyano- S-nitroimidazole Using the method of Example 13 and applying it to 1- oximino-1-[1-(2-benzoyloxyethyl) 5 nitro 2 imidazolyl]-2-phenylglyoxal gives the compound of the example.

We claim: 1. A nitroimidazole of the formula:

wherein R is selected from the group consisting of lower alkyl,

-CH2CH2O(3- lower alkyl and -CII2CH:O fiI-R and R is selected from the group consisting of OCO[R2]R;

-CH=C -CH2CO[R2]R3 and -CCO[RZ]R;

[ fl a NOII wherein R is selected from the group consisting of phenyl, monohalophenyl, dihalophenyl, trihalophenyl, lower alkylphenyl, dilower alkylphenyl, triloweralkyl- 12 phenyl, p-nitrophenyl, naphthyl, trifiuoromethyl, a-pyridyl and lower carbalkoxy and R is selected from the group consisting of R and t-butyl.

2. A nitroimidazole in accordance with claim 1, 1- methyl-5-nitro-a-phenyl 2 imidazoleethenol benzoate.

3. A nitroimidazole in accordance with claim 1, l-ethyl- S-nitro-a-phenyl-Z-imidazoleethenol benzoate.

4. A nitroimidazole in accordance with claim 1, 2-(1- methyl-S-nitro-Z-imidazolyl acetophenone.

5. A nitroimidazole in accordance with claim 1, I-oximino-1-(1-rnethyl-5-nitro-2-imidaz0ly1) 2 phenylglyoxal.

6. A method of preparing a compound of the formula:

N i JI (m c-R wherein R is selected from the group consisting of loweralkyl,

-CH CH Ofi-lower-a1kyl and -CH2CH20G-R2 and R is selected from the group consisting of phenyl, monohalophenyl, dihalophenyl, trihalophenyl, lower alkylphenyl, diloWer alkylphenyl, triloweralkylphenyl, p-nitrophenyl, t-butyl, naphthyl, trifiuoromethyl, d-pyridyl and lower carboalkoxy which comprises reacting l-loweralkyl, l-hydroxy-lower-alkyl, 1-1ower-alkanoyloxy-loweralkyl, or l-benzoyloxy-lower-alkyl 2 methyl 5 nitroimidazole with a compound of the Formula R COX, wherein R is as defined above and X is chlorine, bromine or fluorine, and a tertiary amine in an inert solvent to produce the corresponding enol ester, heating said enol ester with a member selected from the group consisting of lower alkyl alcohols, aqueous acids and aqueous alkalis and recovering the compound therefrom.

References Cited UNITED STATES PATENTS 1,915,334 6/1933 Salzberg et al. 260243 2,075,359 3/1937 Salzberg et al 424250 2,944,061 7/1960 Jacob et al. 260309 HENRY R. JILES, Primary Examiner S. D. WINTERS, Assistant Examiner US. Cl. X.R.

260309, 295 R, 306.8, 308 R, 296 R; 424273 

